Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD

CD4(+)CD25(+) regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4(+)CD25(+) Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4(+)CD25(-) T cells. Here we examined the differential effect of CD62L(+) and CD62L(-) subsets of CD4(+)CD25(+) Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4(+)CD25(-) T cells, only the CD62L(+) subset of CD4(+)CD25(+) Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4(+)CD25(+)CD62L(+) Treg cells were transferred compared with the CD62L(-) subset. Subsequently, CD4(+)CD25(+)CD62L(+) Treg cells showed a significantly higher capacity than their CD62L(-) counterpart to inhibit the expansion of donor CD4(+)CD25(-) T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD. (C) 2005 by The American Society of Hematology